Acute myeloid leukemia (AML) is characterized by increased proliferation, cell death resistance and by a block of the hematopoietic process occurring at different stages of the myeloid differentiation (Meyer S C et al, Lancet Oncol 2014). The impact of several mutations has been explored this last decade, the most frequent being the internal tandem duplication (ITD) in the juxta-membrane domain of the Fms-Like Tyrosine kinase 3 (FLT3), which leads to constitutive activation of this receptor (Nakao M et al, Leukemia 1996). This mutation is particularly associated to normal karyotype AML (Thiede C et al, Blood 2002) and now is part to the most recent prognostic classification of AML (Döhner H et al, Blood 2010). During normal myeloid hematopoiesis, FLT3 is highly expressed and reported to play an important role at the granulo-monocyte progenitor level (Böiers C et al, Blood 2010).
Because of the high frequency of this mutation (25-30% of AML) and of its associated negative prognosis (Thiede C et al, Blood 2002 and Levis M et al, Leukemia 2003), several FLT3 inhibitors have been subsequently developed and tested in different clinical trials, either in combination with chemotherapy or in monotherapy (Wander S A et al, Ther Adv Hematol 2014; Stone R M et al, Leukemia 2012; Serve H et al, JCO 2013; Cortes J E et al, Blood 2012; Levis M J et al, Blood 2012 and Kampa-Schittenhelm K M et al, Mol Cancer 2013). These molecules have a negative impact on AML cells proliferation in vivo, and interestingly, their pro-differentiation effect was also reported clinically, suggesting that inhibiting FLT3-ITD could partially relieve the differentiation arrest occurring in this category of AML (Sexauer A et al, Blood 2012). Recent studies identified the ERK kinase and the cyclin-dependent kinase CDK1 as important players of FLT3-ITD AML differentiation arrest through phosphorylation of the C/EBPα transcription factor on its serine 21 (Zheng R et al, Blood 2004; Radomska H S et al, JExpMed 2006 and Radomska H S et al, JCI 2012), suggesting that CDK or ERK inhibitors could restore the differentiation program of these cells.
CDC25A is a dual specificity phosphatase involved in cyclin-dependent kinases activation during the cell cycle. CDC25A has important functions during replication and mitosis, as well as during the G1 phase of the cell cycle. CDC25A is finely regulated both at the transcription and protein levels (Fernandez-Vidal A et al, Anticancer Agents Med Chem 2008), and moderate variations of its cellular level affect genomic stability and oncogenic transformation process (Ray D et al, Cancer Research, 2008). CDC25A knock-out is lethal at an early stage of embryonic development. Its overexpression was described in different categories of cancers, and was often associated with an adverse prognosis (Boutros R et al, Nat Rev Cancer 2007). However, there is almost no study dealing with CDC25A status in AML or in other myeloid malignancies. CDC25A expression is increased by leukemic cells adhesion to fibronectin, and participates to the adhesion-dependent increased proliferation of these cells (Fernandez-Vidal A et al, Cancer Res 2006). CDC25A is also constitutively expressed downstream of oncogenic tyrosine kinases, including NPM-ALK and BCR-ABL (Fernandez-Vidal A et al, Cell Cycle 2010), as well as JAK2 V617F in myeloproliferative neoplasms (Gautier et al, Blood 2012).
In this invention, inventors demonstrate that CDC25A is an early target of FLT3-ITD oncogenic signaling, and is an important player of AML cells proliferation and differentiation arrest.